The eye is relatively isolated from the rest of the body. The potential scope of adverse effects resulting from treatments targeting the eye is much reduced relative to treatments that enter the body as a whole, or are targeted to one internal organ. Thus eye conditions tend to be a testbed for novel advanced forms of therapy. Further, the state of the more accessible retina is a convenient window into the state of the less accessible central nervous system, and so you'll find researchers focused on retinal cells as a way into gain insight into the mechanisms and progression of neurodegenerative conditions.
In today's open access paper, the authors discuss the effects of multiple sclerosis on the neurons of the retina and optic nerve. Multiple sclerosis is an autoimmune condition characterized by central and peripheral nervous system inflammation and loss of the myelin sheathing needed for nerves to function. The consequent damage also extends to the retina. In an animal model relevant to this pathology, the researchers demonstrate that features of cellular senescence are prevalent in retinal ganglion cells, a type of neuron in the retina. Further, exposure to Yamanaka factors to induce partial reprogramming in retinal cells can reduce this senescence and improve function.
Cellular rejuvenation protects neurons from inflammation-mediated cell death
Multiple sclerosis (MS) is an immune-mediated disease with a neurodegenerative component. While immune-mediated demyelination of axons constitutes a primary pathogenic mechanism in MS, sustained clinical deficits are associated with neuronal degeneration, including loss of neurons in the gray matter and loss of axons in white matter lesions and normal-appearing white matter. Notably, the retina and optic nerve acquire extensive pathology in MS. Optic nerve lesions are frequently detected in patients with MS by MRI. Additionally, there is significant retinal nerve fiber layer and ganglion cell layer thinning evidenced by optical coherence tomography, and this correlates with clinical deficits and brain volume loss. This is mirrored in the experimental autoimmune encephalomyelitis (EAE) mouse model, where there is optic nerve demyelination, immune cell infiltration, and gliosis, retinal nerve layer thinning, neuron loss, and axonal pathology, making the EAE mouse retina and optic nerve a useful model to study inflammation-mediated neurodegeneration.
Recent studies have explored the relationships between aging, cellular senescence, and MS. Cellular senescence is also highly correlated with aging and age-related disease. Although cellular senescence was originally defined by aberrant cell cycle exit, it is also characterized by other features, including altered autophagy, the senescence-associated secretory phenotype (SASP), accumulation of DNA damage, and epigenetic changes. Targeting aging and senescence programs in MS may be a beneficial strategy to address immune cell or glial dysfunction; however, there is limited data about the neuronal gene signature in MS and thus whether rejuvenating therapies may promote neuroprotection.
Here, we profile the transcriptome of retinal ganglion cells (RGCs) in EAE mice. Pathway analysis identifies a transcriptional signature reminiscent of aged RGCs with some senescent features, with a comparable signature present in neurons from patients with MS. This is supported by immunostaining demonstrating alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 adeno-associated virus (AAV) to rejuvenate the transcriptome enhances RGC survival in EAE and improves visual acuity. Collectively, these data reveal an aging-like phenotype in neurons under pathological neuroinflammation and support the possibility that rejuvenation therapies or senotherapeutic agents could offer a direct avenue for neuroprotection in neuroimmune disorders.
View the full article at FightAging
